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HYPOTHESIS AND THEORY published: 04 January 2017 doi: 10.3389/fnins.2016.00595

An Evolutionary Hypothesis of Binary Opposition in Functional Incompatibility about Habenular Asymmetry in Vertebrates

Hiroyuki Ichijo *, Tomoya Nakamura, Masahumi Kawaguchi and Yuichi Takeuchi

Department of Anatomy and Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

Many vertebrates have asymmetrical circuits in the nervous system. There are two types of circuit asymmetry. Asymmetrical circuits in sensory and/or motor systems are usually related to lateralized behaviors. It has been hypothesized that spatial asymmetry in the environment and/or social interactions has led to the evolution of asymmetrical circuits by natural selection. There are also asymmetrical circuits that are not related to lateralized behaviors. These circuits lie outside of the sensory and motor systems. A typical example Edited by: is found in the habenula (Hb), which has long been known to be asymmetrical in many Robert D. Rafal, vertebrates, but has no remarkable relationship to lateralized behaviors. Instead, the University of Delaware, USA Hb is a hub wherein information conveyed to the unilateral Hb is relayed to diverging Reviewed by: Ronen Segev, bilateral nuclei, which is unlikely to lead to lateralized behavior. Until now, there has Ben-Gurion University of the Negev, been no hypothesis regarding the evolution of Hb asymmetry. Here, we propose a new Israel Oren Poliva, hypothesis that binary opposition in functional incompatibility applies selection pressure Bangor University, UK on the habenular circuit and leads to asymmetry. Segregation of the incompatible *Correspondence: functions on either side of the habenula is likely to enhance information processing Hiroyuki Ichijo ability via creating shorter circuits and reducing the cost of circuit duplication, resulting in [email protected] benefits for survival. In zebrafish and mice, different evolutionary strategies are thought Specialty section: to be involved in Hb asymmetry. In zebrafish, which use a strategy of structurally fixed This article was submitted to asymmetry, the asymmetrical dorsal Hb leads to constant behavioral choices in binary Systems Biology, a section of the journal opposition. In contrast, in mice, which use a strategy of functionally flexible lateralization, Frontiers in Neuroscience the symmetrical lateral Hb is functionally lateralized. This makes it possible to process Received: 13 September 2016 complicated information and to come to variable behavioral choices, depending on the Accepted: 14 December 2016 specific situation. These strategies are thought to be selected for and preserved by Published: 04 January 2017 Citation: evolution under selection pressures of rigidity and flexibility of sociability in zebrafish Ichijo H, Nakamura T, Kawaguchi M and mice, respectively, as they are beneficial for survival. This hypothesis is highly and Takeuchi Y (2017) An Evolutionary valuable because it explains how the Hb evolved differently in terms of asymmetry and Hypothesis of Binary Opposition in Functional Incompatibility about lateralization among different species. In addition, one can propose possible experiments Habenular Asymmetry in Vertebrates. for the verification of this hypothesis in future research. Front. Neurosci. 10:595. doi: 10.3389/fnins.2016.00595 Keywords: scale-eating, zebrafish, mouse, habenula, asymmetry, lateralization, natural selection

Frontiers in Neuroscience | www.frontiersin.org 1 January 2017 | Volume 10 | Article 595 Ichijo et al. Evolution of Habenular Asymmetry

INTRODUCTION

Brain asymmetry and functional lateralization are recognized in many vertebrates. It is well-known that the left side of the cerebral hemisphere is dominant in language in most humans, especially in right-handed persons (Wada and Rasmussen, 1960; McGlone, 1984). Higher brain functions are differentiated based on brain hemisphere. Brain lateralization has been experimentally analyzed. The results of such experiments indicate that social cognition and interactions between predator and prey are involved in lateralized animal behaviors. The most well-known example of lateralized behavior in a neuronal circuit is found in birds, especially in the chick visual system (Rogers and Anson, 1979; Rogers, 1982, 2000; Evans et al., 1993; Rogers and Andrew, 2002). At the behavioral level, the chick utilizes the left and right eyes differently, depending on the situation. Chicks tilt their heads, using mainly their left eye to see the sky. They thus use the left eye for detecting flying predators. The left eye and the downstream visual circuits, which cross to the right side of the optic tectum, are more sensitive to moving objects. On the other hand, chicks see the ground mainly using their right eye, which is used for searching for feed on the ground. The right eye and the left optic tectum are more sensitive to fine features. Lateralization of the visual system enables chicks to perform different tasks independently and simultaneously. Lateralized circuits make parallel processing of different visual FIGURE 1 | Two levels of asymmetry: individual asymmetry and information possible and increase the probability of survival for population asymmetry, and their examples in heart formation. The heart the chick. Therefore, lateralized behavior is naturally selected for tube is originally symmetrical (A). The heart tube undergoes asymmetrical and implemented in the structures of the asymmetrical circuits. morphogenesis. This consists of dextral or sinistral looping, which makes the heart asymmetrical. Dextral looping causes , where the heart lies on Before discussing asymmetry at different levels, we will the left side of the thorax. On the other hand, sinistral looping causes define the following terms: individual asymmetry, population , where the heart lies on the right (individual asymmetry) (B). In asymmetry, and direction of asymmetry. We will explain these human populations, almost all individuals have levocardia (population terms using examples of a well-known asymmetrical structure, asymmetry), with the direction of the asymmetry toward the left side. Coinciding with , dextrocardia occurs in about 1/7000 the heart, which is a part of the cardiovascular system. In individuals. Thus, the heart exhibits asymmetry with a population bias of the beginning of heart formation, a symmetrical heart tube 7000:1 (levocardia vs. dextrocardia) (“degree of direction” or “population bias undergoes dextral looping, resulting in an S-shaped heart of direction”) (C). tube and leading to the formation of an asymmetrical heart (Figures 1A,B). The dextral looping causes levocardia, which causes the heart to lie on the left side of the thorax. Therefore, the population is represented by the “degree of the direction” or the heart is asymmetrical in all individuals. “Individual asymmetry” “population bias of the direction.” Thus, the heart exhibits an means that the left and the right sides are asymmetrically different asymmetry of levocardia or dextrocardia with a population bias in individuals. In almost all individuals in the human population, of 7000:1, which indicates that heart asymmetry is highly biased the heart tube undergoes dextral looping. However, in rare toward the left. cases, it undergoes looping in the opposite direction. Sinistral In the nervous system, symmetry breaking is usually observed looping causes dextrocardia, which is when the heart lies on in two ways: structures and behavior. Thus, the words asymmetry the right. “Population asymmetry” means that individuals with and lateralization are often used differentially. Considering the hearts on one or the other side are more predominant in the links between the structures/functions of circuits and behavior, population (Figure 1C). “Direction of asymmetry” represents it is understandable that asymmetrical structures/functions of the predominant side. Coinciding with situs inversus, in which neuronal circuits direct lateralized behaviors, which interact with the visceral organs are mirrored from their normal positions, the environment in an asymmetric manner. Even when circuits dextrocardia occurs in about 1/7000 individuals (Sadler, 2004). are structurally symmetrical, they may be used asymmetrically. The ratio of the left- or right-sidedness of the organs in the This results in functional lateralization, which can lead to lateralized behavior. Thus, we need to discriminate between Abbreviations: Hb, habenula; FR, fasciculus retroflexus; DHb, dorsal habenular structural asymmetry and functional lateralization when nucleus; VHb, ventral habenular nucleus; DHbM, medial subnucleus of DHb; DHbL, lateral subnucleus of DHb; IPN, interpeduncular nucleus; vIPN, ventral we analyze behavioral lateralization. In general, the word region of IPN; dIPN, dorsal region of IPN; MHb, medial habenular nucleus; LHb, “asymmetry” is usually used to describe structures and lateral habenular nucleus; DA, dopamine; 5-HT, serotonin. “lateralization” is used to describe functions and/or behaviors.

Frontiers in Neuroscience | www.frontiersin.org 2 January 2017 | Volume 10 | Article 595 Ichijo et al. Evolution of Habenular Asymmetry

Functional and behavioral lateralizations are similar, but are not exactly equivalent. For example, in mice, the Hb is lateralized, but there is no remarkable behavioral lateralization (Ichijo et al., 2015). It is also logically possible that asymmetrically structured circuit is functionally lateralized in a manner that leads to no lateralized behavior. Because functional lateralization does not necessarily generate lateralized behavior, we will use the terms lateralization of function and lateralization of behavior as terms with distinct meanings in this article. There are at least two different types of circuit asymmetry and lateralization to be discussed in the nervous system. The first type is on the circuits related to lateralized behaviors in the sensory and motor systems. Asymmetrically structured and/or functionally lateralized circuits in the sensory systems are involved in asymmetrically capturing information from the outer world, as is shown in the lateralized usage of the visual system in chicks. And asymmetrical or lateralized circuits of FIGURE 2 | Structural asymmetry and behavioral lateralization of the scale-eating fish, Perissodus microlepis. The behavioral lateralization in the motor systems may be involved in outputting information predation is shown. The lefty fish, with tilting mouth with larger left mandibular to the outer world in an asymmetric manner as lateralized bone preferentially attack the left flank of the prey fish. The righty fish, with behaviors. In the next section, which concerns the scale-eating larger right mandibular bone have the opposite behavior (A). The mouths of cichlid fish in Lake Tanganyika, we review a current hypothesis the scale-eating fish tilt to one side or the other with respect to the body axis. regarding the evolution of lateralized behaviors. This hypothesis The dots indicate the lateral tip of the mouth in the dorsal view of head (B). In the lefty scale-eating fish, the left mandibular bone is larger than the right. states that spatial asymmetry in environment and/or social Arrows represent the height of the entire posterior dimension of the mandibular interaction is thought to apply its natural selection pressure on bone (C). L, left; R, right. Scale bars, 1 cm (B), and 1 mm (C). the interfaces of sensory and/or motor circuits (Ghirlanda and Vallortigara, 2004; Ghirlanda et al., 2009). These include the lateralized predation behaviors of the scale-eating cichlid fish. equal, but are subtly different from each other at any point. Such lateralized behaviors are under the influences of predators, The proportions of the lefty and righty fish oscillate around prey, or other individuals in the environment. 50%, with a period of 4–5 years, and an amplitude of 15%. The second type is on the circuits without remarkable relation Thus, the proportions fluctuate between 65:35% and 35:65%. to lateralized behaviors. In the last three sections, we consider Because the prey eventually learns to predict the attacks of the evolution of the Hb, which is in the epithalamus of the the cichlid fish on one side, cichlid fish in the majority have diencephalon. The Hb has long been known to be asymmetrical less of a chance to attack. This reduces the chance for the in many vertebrates and is not related to lateralized behavior. majority of the fish to survive and have offspring. On the Thus, one is faced with the difficulty of explaining how the Hb other hand, individuals in the minority have a greater chance has evolved. We have two aims in this article. One is to point of attacking prey, as the prey does not expect an attack from out that the current evolutionary hypothesis regarding behavioral the opposite side. This increases the chance for the minority lateralization is not applicable to the Hb. The other is to to survive and have offspring, eventually. Thus, individuals propose the new hypothesis that binary opposition in functional of the minor phenotype are going to be more successful as incompatibility applies selection pressure to the asymmetrical predators than those of the major phenotype. Therefore, it has circuit of the Hb. been suggested that the oscillations in the proportions of the lefty and righty fish are maintained by negative frequency- LATERALIZED BEHAVIORS UNDER THE dependent selection (Hori, 1993; Takahashi and Hori, 1994). INFLUENCE OF SOCIAL INTERACTIONS IN Although the lefty and righty fish are always competing with each other, this competition generates heterogeneity of lateralized AN EVOLUTIONARY STABLE STRATEGY: behaviors in the species, which is stable in social interactions. THE EXAMPLE OF THE SCALE-EATING This heterogeneity thus increases the chances for survival and CICHLID FISH IN LAKE TANGANYIKA contributes to the maintenance of the species as a whole. The lefties and the righties antagonistically interact with each other. A scale-eating cichlid fish in Lake Tanganyika, Perissodus In other words, prosperity of the majority (e.g., the lefty) is microlepis, exhibits lateralized behavior of predation (Hori, inhibited by the prosperity of the minority (e.g., the righty). 1993). The cichlid fish is specialized to forage predominantly This antagonistic interaction within the species influences the on the scales of the other fish (Fryer and Iles, 1972). About directional bias of lateralization to remain around 50:50. The 50% of scale-eating cichlid fish in the field always attack and results obtained from the studies in the scale-eating cichlid fish snatch scales from the left side of a prey (lefties), while the strongly support the theory of directional lateralization as an other fish attack the right (righties) (Figure 2A). The numbers evolutionally stable strategy. This theory states that population of individuals in the lefty and the righty groups are not precisely bias of the direction is determined by the degrees of synergistic

Frontiers in Neuroscience | www.frontiersin.org 3 January 2017 | Volume 10 | Article 595 Ichijo et al. Evolution of Habenular Asymmetry or antagonistic effects in the lateralized behaviors in social selection pressure common among different species from fish interactions (Takahashi and Hori, 1994). to mammals. The Hb is situated in the middle of the neuronal Not only behavioral lateralization but also structural circuit between the telencephalon and the mesencephalon. It asymmetry is found in the mouth (Liem and Stewart, 1976) and receives information concerning various aspects of emotion, such the mandibular bone (Takeuchi et al., 2016), which is crucial as failure, punishment, and stress, from the basal ganglia and the for the success of the scale-eating (Figures 2B,C). In a recent limbic system in the telencephalon through the stria medullaris report, structural asymmetry of the mouth is proposed to be unilaterally (Herkenham and Nauta, 1977; Matsumoto and inherited through multiple loci (Raffini et al., 2016). Thus, the Hikosaka, 2007). Axons derived from the Hb run unilaterally and asymmetrical body structure is under genetic control and its ventrally, forming a pair of thick axonal bundles on both sides. responsible genes are thought to be under natural selection Each of these bundles is called the fasciculus retroflexus (FR) and pressure. projects to midline nuclei in the mesencephalon (Herkenham It is also expected that neuronal circuits responsible and Nauta, 1979; Figure 3). Thus, the Hb is a hub wherein for the lateralized predation behavior of scale-eating are information conveyed to the unilateral Hb is relayed to nuclei naturally selected by bilateral pressure from the outer that diverge bilaterally. This is likely to induce overall behavioral world (disruptive selection; Rueffler et al., 2006) and exhibit asymmetrical structures and/or lateralized functions. However, a corresponding asymmetry has not yet been identified in neuronal circuits. The scale-eating fish approach their prey from a specific side. Thus, it is plausible that they use their visual system laterally, corresponding to the side they approach their prey. Subsequently, the lateralized predation behavior results from the output command of the motor system. Since the predation behavior is similar to the C-shaped escape behavior, their underlying circuits may be similar (Takeuchi et al., 2012). This possibility raises the chance to find an asymmetrical structure and/or a lateralized function in motor systems corresponding to the predation behavior. Therefore, the scale-eating fish could be an ideal field of study, pursuing neuronal mechanisms underlining lateralized behaviors. Findings of lateralized behaviors in the cichlid fish strongly support the currently accepted hypothesis that the direction of behavioral lateralization is under the control of an evolutionally stable strategy (Ghirlanda and Vallortigara, 2004; Ghirlanda et al., 2009; Rogers et al., 2013). In this hypothesis, first, it is supposed that genes govern the generation of asymmetrical structures. Second, it is hypothesized that asymmetry or lateralization in the brain manifests as lateralized behaviors with left-right bias. Finally, it is thought that social interactions resulting from lateralized behaviors, such as interactions between individuals or between predators and prey, lead to natural selection pressures and generate population biases in asymmetry in and/or lateralization of the central nervous system. However, there are examples of structural asymmetry under the influences of natural selection pressure of social interactions in the absence of lateralized behaviors that cannot be explained by the current hypothesis. In the following sections, we consider these cases FIGURE 3 | The habenula (Hb) as a hub of circuit, where information is converged unilaterally and then diverged bilaterally. Each side of the Hb and propose a new hypothesis for the generation of asymmetrical receives inputs mainly from the limbic system and the basal ganglia through circuits. the same side of stria medullaris. The Hb sends outputs unilaterally and ventrally to the interpeduncular nucleus and the brain structures containing dopaminergic neurons and serotonergic neurons in ventral mesencephalon ASYMMETRY OF THE HABENULA IN through fasciculus retroflexus. Monoaminergic nuclei send output diffusely and ZEBRAFISH AND HYPOTHESIS OF BINARY bilaterally to the many targets including the telencephalon. Many other connections are not shown, including reverse connections (e.g., from OPPOSITE BEHAVIORS IN FUNCTIONAL monoaminergic system to Hb) and commissural connections between the INCOMPATIBILITY telencephalons (e.g., , anterior commissure, and posterior commissure). Hb, habenula; IPN, interpeduncular nucleus; DA, dopaminergic The Hb is highly conserved in vertebrates. This suggests that its nuclei (e.g., ventral tegmental area and substantia nigra pars compacta); 5-HT, serotonergic nuclei (e.g., dorsal raphe and median raphe nuclei). function is essential for survival and under influence of natural

Frontiers in Neuroscience | www.frontiersin.org 4 January 2017 | Volume 10 | Article 595 Ichijo et al. Evolution of Habenular Asymmetry changes via bilateral projection systems, but is unlikely to cause of the DHb to that of a switchboard. The DHb is not involved lateralized behavior. In addition to its conserved structure, the in lateralized behaviors. Its role is neither similar to the sensory Hb is well-known to exhibit structural asymmetry in many circuits for the asymmetrical usage of the eye in birds (Rogers and vertebrates (Concha and Wilson, 2001). In zebrafish, the Hb Anson, 1979; Rogers, 1982, 2000; Sandi et al., 1993), nor to the consists of two different nuclei, the dorsal and the ventral motor circuits assumed in the lateralized behaviors of scale-eating Hb (DHb and VHb; Concha et al., 2000, 2003; Gamse et al., cichlid fish (Hori, 1993; Takahashi and Hori, 1994; Takeuchi et al., 2003; Aizawa et al., 2005; Amo et al., 2010; Figure 4A). The 2012, 2016). Unlike sensory and motor circuits, the DHb is likely DHb is composed of medial and lateral subnuclei (DHbM to participate in the circuit processing binary opposite behaviors and DHbL). These subnuclei are connected topographically to that are functionally incompatible. different parts of the interpeduncular nucleus (IPN) in the ventral The term “functional incompatibility” means that the mesencephalon. The DHbM is connected to the ventral IPN mechanisms adequate for the solution of one problem are (vIPN) and the DHbL is connected to the dorsal IPN (dIPN). The incompatible with those needed to resolve another problem DHbM and the DHbL exhibit asymmetry between their left and (Rogers et al., 2013). The incompatibility between escaping and right side. On the right side, the DHbM is large but the DHbL is freezing prevents the fish from swimming against threats, which small while on the left side, the DHbL is large but the DHbM is is beneficial for their survival. The incompatibility between small. This asymmetry is with near 100% population bias except winning and losing behaviors causes the fish to avoid fatal for the cases of situs inversus. fights and enables them to establish a social hierarchy, which is Various roles have been reported for the Hb (Brady and beneficial for the survival of each individuals and maintenance Nauta, 1955; Rausch and Long, 1974; Thornton and Bradbury, of the group. Thus, it is reasonable that these incompatibilities 1989). For example, the DHb is thought to be involved in the are favored by natural selection. The structures and functions regulation of behaviors induced by fear. Expressing the tetanus of neuronal circuits for binary opposite behaviors are thought toxin light chain specifically in the DHbL, Agetsuma et al. (2010) to be under natural selection pressure resulting from functional genetically inactivated the DHbL to study its role in behavior. incompatibility. The functional incompatibility among logical In the fear-conditioning response, fish with inactivated DHbLs demands is hypothesized to underlie the evolution of multiple do not escape, but freeze instead, indicating that cessation of systems in biology (Sherry and Schachter, 1987). the escaping behavior is functionally linked to the generation There would be two requirements for making the animals of the freezing behavior. Thus, the DHbL is involved in the to engage in incompatible behaviors. The first requirement binary choice between escaping and freezing. However, it is not would be separation; the incompatible behaviors are processed clear how the fish choose the alternative behavior of freezing separately in each circuit. The second would be mutual instead of escaping when the DHbL is inhibited. Chou et al. inhibition; one circuit inhibits the other and vice versa. Thus, (2016) inactivated the DHbL or the DHbM genetically and it is thought that a set of separated circuits mutually inhibiting studied their effects on fighting behavior between two fish during each other has evolved in organisms (Figure 4B). In the a social conflict. Fish with inactivated DHbL tended to lose, first requirement, functional incompatibility may be separated even though their physical strengths, anxiety levels, locomotion through asymmetry during evolution. From a computational activities, and aggressiveness were similar to those of wild type point of view, it has been suggested that segregation of functions fish. On the other hand, fish with inactivated DHbM tended in the halves of the brain is likely to enhance ability of to win. These results indicate that information in the pathway information processing by decreasing its circuit path and reduce involving the DHbL and the DHbM is involved in typical the cost of duplicating circuits, resulting in greater benefits for behaviors during social conflict. This suggests that the DHb survival. This represents a solution to the problem of functional functions in binary behaviors during social conflicts. The two incompatibility (Vallortigara et al., 1999), and such concept was experiments: fear-conditioning responses (escaping or freezing) confirmed by experimental evidences in zebrafish (Agetsuma and responses to aggression during social conflict (winning or et al., 2010; Chou et al., 2016). Indeed, the incompatible behaviors losing), seem very different from each other. However, these of escaping/freezing and winning/losing are processed in the experiments provide us with clues for understanding the role asymmetrical left and right nuclei of the DHb. Thus, it is of DHb. The distinct behaviors are represented in the same very likely that the DHb is the nucleus representing functional nucleus. This indicates that the DHb is not involved in specific incompatibility and that its asymmetrical structure ensures behaviors, such as escaping/freezing or winning/losing. Instead, separation of the binary opposition. One may then ask where the it is plausible that the DHb is involved in mechanisms that DHb is placed in the circuits of functional incompatibility and are common between escaping/freezing and winning/losing, what its role is. where both sets of behaviors are in binary opposition. The fish In the upstream circuits of the DHb, information from the cannot perform these behaviors simultaneously, but must choose environment, such as threats or social conflict, is assessed in one behavior over the other. Impairment of the DHbL during the sensory systems, the amygdala, and the extended amygdala. fear-conditioning caused the fish to choose freezing instead of The inactivation of the extended amygdala in mice (the bed escaping. During social conflict, impairments of the DHbL and nucleus of the stria terminalis) resulted in an ignorance of the the DHbM made the fish to perform opposing behaviors; DHbL smell of a predator, and the mice did not escape or freeze. impairment led to losing, and DHbM impairment led to winning. This indicates that the bed nucleus of the stria terminalis is Agetsuma et al. (2010) and Chou et al. (2016) likened this aspect involved in the early steps in the processing of functional

Frontiers in Neuroscience | www.frontiersin.org 5 January 2017 | Volume 10 | Article 595 Ichijo et al. Evolution of Habenular Asymmetry

FIGURE 4 | Schematic drawing of habenular asymmetry and a circuit model for functional incompatibility in zebrafish. (A) The dorsal habenula nucleus (DHb) is subdivided into medial and lateral subnuclei (DHbM and DHbL, respectively). The DHbM is larger on the right side than on the left side. The DHbL is larger on the left side than on the right side. They are connected to different parts of the interpeduncular nucleus (IPN). The DHbM is connected to the vIPN and the DHbL is connected to the dIPN. (B) There are two requirements for functional incompatibility: separation and mutual inhibition. In this model, the hypothetical mutual inhibition is supposed to be situated downstream of the DHb, where the impairment of the DHbM or the DHbL causes opposing behaviors. Because the DHbM and DHbL are asymmetrically separated on the right and left, the two circuits are asymmetrically structured on the right and the left. The experimental evidence by Agetsuma et al. (2010) and Chou et al. (2016) favor this model. DHb, dorsal habenular nucleus; DHbM, medial subncleus of dorsal habenular nucleus; DHbL, lateral subncleus of dorsal habenular nucleus; VHb, ventral habenular nucleus; dIPN, dorsal region of interpeduncular nucleus; vIPN, ventral region of interpeduncular nucleus. incompatibility (Kobayakawa et al., 2007). It is thought that the As for the second requirement, mutual inhibition must occur information is processed differentially based on its importance downstream of the DHb because genetic inactivation of the (e.g., predator or not) and amount (e.g., intensity of the smell). DHb resulted in alternative behaviors in binary opposition This is then thought to result in the binary outputs inducing (escaping/freezing and winning/losing) (Figure 4B). However, incompatible behaviors. Because the DHb receives fibers of the the mutual inhibition has not yet been found in pathways stria medullaris unilaterally, the information is thought to be involving the DHb. Although Chou et al. (2016) indicated that separately lateralized in upstream structures before arrivingatthe there is no neural connections between the DHbL and the DHbM DHb. The functional lateralization might be generated between or between the dIPN and the vIPN, the connection should be the extended amygdala and the Hb. Thus, there is a possibility hidden in other unknown place. that the binary opposite behaviors are generated not only in Taking all of the above into consideration, we propose the the DHb but also in the circuit chain to the DHb. To examine hypothesis of binary opposition in functional incompatibility to this possibility, it would be informative to look for functional explain the evolution of asymmetry in the Hb. Even without lateralization in the upstream of the Hb. In addition, because lateralized behaviors, the asymmetrical Hb is thought to have the DHb is involved in incompatible behaviors and is situated evolved under the natural selection pressure resulting from in the upstream of mesencephalic nuclei, such as the IPN and functional incompatibility. Because it is essential for survival and the monoaminergic nuclei, which modulate various aspects of under the common selection pressure, the asymmetrical Hb is behavior, it is thought to participate in circuits near to the thought to be broadly conserved in vertebrates. In zebrafish, execution of binary opposite behaviors. Nodal signaling plays pivotal roles in determining the direction

Frontiers in Neuroscience | www.frontiersin.org 6 January 2017 | Volume 10 | Article 595 Ichijo et al. Evolution of Habenular Asymmetry of the Hb asymmetry (Concha et al., 2000, 2003; Aizawa et al., species or not. Therefore, not only the asymmetry itself, but also 2005; Carl et al., 2007; Inbal et al., 2007). the directions, the degrees, and the strengths of the asymmetry While Hb asymmetry is conserved, directions, and degrees may be evolved under the selection pressure resulting from of its asymmetry differ among species (Concha and Wilson, functional incompatibility (the hypothesis of binary opposite 2001). Villalón et al. (2012) analyzed interspecies differences in behaviors threshold about the direction of Hb asymmetry). This DHb asymmetry in seven species of teleost fish, although they may also indicate that diversity of the directions among the did not differentiate between the DHbM and the DHbL. In all species is under the influences of selection pressures different in species examined, the DHb exhibited asymmetry. This again social interactions and/or environments. Both the genetic drift indicates that the selection pressure of functional incompatibility hypothesis and the natural selection hypothesis can be examined has been commonly and consistently exerted on the DHb and experimentally in the future (Lamichhaney et al., 2016). made this structure to be asymmetrical. However, the direction of its asymmetry varies among different species. In Danio rerio (D. rerio, zebrafish), Epalzeorhynchos bicolor (E. bicolor, redtail SYMMETRY OF THE HABENULA IN MICE sharkminnow), Oryzias latipes (O. latipes, medaka), Poecilia AND ITS LATERALIZATION reticulata (P. reticulata, guppy), and Betta splendens (B. splendens, Siamese fighting fish), the left DHb is larger than the right. The In spite that basic cytoarchitecture of the Hb is conserved, left-right difference is more remarkable in D. rerio and E. bicolor, the mammalian Hb shows structural symmetry exceptionally but is moderate in O. latipes. This shows that left side bias has (Concha and Wilson, 2001). The mammalian Hb consists of the varying strengths in population asymmetry. In Fundulopanchax medial (MHb) and lateral habenular nuclei (LHb), which are gardneri (F. gardneri, Steel-blue Killifish) females, the right homologous to the zebrafish DHb and VHb, respectively (Amo DHb is larger than the left, which indicates a right side bias. et al., 2010). Similar to zebrafish, the Hb axons form the FR. Additionally, in F. gardneri males and in Pterophyllum scalare In the FR, the axons from different origins are topographically (P. scalare, angelfish), one side of the DHb is larger than the other, organized. The axons from the MHb run in the core of the FR although the larger side is different in each fish. This indicates and project to the IPN. On the other hand, the axons from the individual asymmetry with no population bias. LHb run in the sheath of the FR (Herkenham and Nauta, 1979; The mechanism by which the direction of DHb asymmetry Ichijo and Toyama, 2015), sending outputs to outside the IPN: is determined remains unknown. However, we propose the the dopaminergic (DA) and the serotonergic (5-HT) nuclei. following two hypotheses. One is based on a stochastic idea, Using a simple transgene with a long half-life fluorescent which states that the direction is under the influence of genetic protein (Venus) under the control of an immediate early gene drift (the hypothesis of genetic drift about the direction of (zif268/egr1) promoter, we labeled the history of neuronal activity Hb asymmetry). Genetic drift leads to fluctuations in gene and found that the LHb is functionally lateralized in mice (Ichijo frequencies affecting Hb asymmetry, making either side of the et al., 2015). During the immature stage around postnatal day Hb dominant with no advantage nor disadvantage for survival 13 (P13), the sheath of the FR was unilaterally labeled by the (Lande, 1985; Barton and Rouhani, 1987). This fluctuating history of neuronal activity in the LHb. The unilateral labelings asymmetry is thought to be stabilized in the group because of in the FR were observed up to P20, but not after P35. Expression the low probability of its reversal. This may lead to interspecies of intrinsic ZIF268/EGR1 proteins in the LHb was lateralized differences in the direction of the asymmetry. The other around P13. Thus, activation of the LHb induced by stress hypothesis is based on a concept of natural selection that selection caused unilateral labeling of the FR. The lateralization was not pressures resulting from functional incompatibility determines biased to either side at the population level (left, 45.8%; right, the directions. Even though the directions are diverse, laterotopic 54.2%; n = 72). In addition, there was no sexual difference projections are conserved; the left DHb projects to the dorsal between males and females (male: left, 45.9%; right 54.1%; IPN, and the right DHb projects to the ventral IPN (Villalón n = 37; female: left, 45.7%; right 54.3%; n = 35). Thus, the et al., 2012). This indicates that information passageways are kept symmetrical LHb is functionally lateralized without directional separated and are wired to the same downstream targets. The bias or sexual differences during postnatal development and in conserved wiring enables the organisms to process information the stress response in mice. for binary opposite behaviors in a similar manner. Assuming that Careful examinations of the labelings showed that one the subnuclear organization of the DHb is common between D. side of the FR was not exclusively labeled. Instead, one side rerio (zebrafish) and other species, the interspecies differences was more intensely labeled than the other side. Furthermore, in the directions suggest that the dominances of the DHbL neither side of the FR was equally labeled in any of the mice or the DHbM vary among the species. This may indicate examined. The segments of the FR were often labeled alternately that behaviors in binary opposition (e.g., escaping/freezing and between the left and right FR along the dorsoventral axis winning/losing) do not occur over the same threshold, but are (Figures 5A,B). Because of the growth associated protein-43 displayed under different thresholds in each species, leading to (GAP-43) membrane localization sequence linked to Venus, the differential sociability (Bisazza et al., 2000). In this sense, the labeling was localized to the cell surface. Generally, in axon questions proposed by Villalón et al. (2012) and Chou et al. tracing experiments using lipophilic membranous tracers, if (2016) are highly valuable, whether the directions of the DHb given enough time, a large amount of the tracers labels entire asymmetry are related to differences in sociability among the neurons from the soma to axon terminals. However, a small

Frontiers in Neuroscience | www.frontiersin.org 7 January 2017 | Volume 10 | Article 595 Ichijo et al. Evolution of Habenular Asymmetry

FIGURE 5 | Alternate labeling and temporal shift of the labeling in between the left and the right fasciculus retroflexus (FR) reflecting the history of LHb neuronal activity. The segments of the FR are labeled alternately between the right and left at P11 (A) and P13 (B). In case A (P11), the right FR is dominantly labeled. Dorsoventral courses of the FR are shown in successive coronal sections of mouse diencephalon from the anterior (1) to the posterior (6). The history of neuronal activity is labeled in green. Cytoarchitecture is visualized in purple by the fluorescent Nissl stain. The right FR is indicated by arrows. The left FR is indicated by arrowheads. The labeled FRs are indicated as black arrows and black arrowheads, on the right and left, respectively. In case B (P13), the left FR is dominantly labeled. During development, the right FR is dominantly labeled in the early phase at P11 and P12. Then, the left FR labeling appears in the late phase at P13 and thereafter (C). In responses to stress, the right FR is dominantly labeled in the early phase, which is 6 h after stress. Then, the left FR labeling appears in the late phase, 24 h after stress (D). MHb, medial habenular nucleus. LHb, lateral habenular nucleus. R, right; L, left. Scale bars, 500 µm. (C,D) Ichijo et al. (2015) with permission from Elsevier. amount only labels parts of the axons (Ichijo, 1999; Ichijo and that LHb lateralization is caused by oscillatory activation between Toyama, 2015). Therefore, in our experiments, the LHb neurons the right and the left. Further functional investigations would be may have transiently produced an insufficient amount of Venus informative in the study of the nature of LHb lateralization. Until protein that is only enough to label segments of the FR. In recently, functional lateralization of the mammalian Hb had not addition, there is a tendency that the right FR is labeled in the been described. However, a fMRI study in humans has indicated early phase, while left FR labeling appears to occur in the late that the Hb is lateralized. Specifically, the activities of the left phase. The shift of the labeling between the right and the left from and the right Hb were shown to be not correlated and the left the early to the late stages is common during development and and the right Hb were shown to be functionally connected to in response to the stress. The right FR is labeled at P11 during different brain areas, although the MHb and the LHb were not development and at 6 h after stress. Left FR labeling appears at distinguished (Hétu et al., 2016). P13 during development and at 24 h after stress (Figures 5C,D). The Hb receives information about cognition and emotion The observations of: (1) spatial alternations in labeling of the FR related to the external and internal states of the animal. segments between the right and left, and (2) the temporal shift of Such information includes sensory/motor, reward, arousal, and the labeling from early in the right to late in the left are suggestive emotion/stress data. This information originates mainly in the of oscillation. In the mouse, the direction of lateralization of the basal ganglia and the limbic system in the telencephalon and LHb may not be restricted to one side or the other. Instead, the is projected to the Hb through the unilateral stria medullaris LHb may be dynamically activated between the right and the (Herkenham and Nauta, 1977; Araki et al., 1984; Figure 3). left during the time course of its activation. It is thus possible From this lateralized input, the LHb integrates the information

Frontiers in Neuroscience | www.frontiersin.org 8 January 2017 | Volume 10 | Article 595 Ichijo et al. Evolution of Habenular Asymmetry and provides a passageway to monoaminergic neuromodulator in binary opposition. This leads to higher reproducibility in systems in the ventral mesencephalon. It sends outputs to the individual behaviors of fish organized in the group, producing DA nuclei of the ventral tegmental area and the substantia consistent social interactions. From the social point of view, nigra pars compacta through the rostromedial tegmental nucleus. because incompatible behaviors are highly organized, the social It also sends outputs to the 5-HT nuclei of the dorsal and interactions between zebrafish are thought to be relatively simple, median raphe nuclei (Herkenham and Nauta, 1979; Araki et al., consistent, and rigid with little room for adjustment. This may 1988; Yañez and Anadón, 1996; Jhou et al., 2009; Kaufling lead to selection pressure on the fixed circuits and result in an et al., 2009; Figure 3). They diverge information bilaterally, asymmetrically structured DHb. influencing functions of broad targets, influencing the choices for In contrast, mice are thought to have adopted a functionally relevant adaptive behaviors, and switching between goal-directed flexible strategy, which enables them to perform variable behaviors (Baker et al., 2015). The information conveyed to the behaviors and possibly produce flexible social interactions. From unilateral LHb is likely to induce behavioral changes through the the circuit point of view, the lateralized usage of the symmetrical bilateral projection systems of the DA and 5-HT, but unlikely to LHb makes it possible to process complicated information cause lateralized behavior. Because the LHb receives input from for goal-directed behavioral choices. Various information in the unilateral stria medullaris, upstream circuits must be already environment is likely to be used for the estimation of reward- functionally lateralized. prediction errors, which could cause variable behavioral choices When LHb activity is regulated, animals are typically in opposition. Because the LHb is functionally lateralized in confronted with opposing behavioral choices, such as moving every mice, each mouse is likely to exhibit variable behavior to seek rewards or not moving to avoid negative consequences. depending on the circumstances. This would lead to the During such decision making, the LHb regulates target nuclei control of individual behaviors in the group (Matsumoto and in the DA and 5-HT systems (Matsumoto and Hikosaka, 2007; Hikosaka, 2007; Hikosaka, 2010). Thus, it is hypothesized that Hikosaka, 2010). The LHb seems to have general roles in the lateralization of the LHb is important in dynamic regulation behavioral choices. Baker et al. (2015) proposed that, when the of behavioral choices. Functional regulation of behavioral choices switching of behavioral strategies is required, the LHb plays a is beneficial for mice because it increases their survival, even role in the execution of goal-directed behaviors and is involved though it leads to the increased costs of circuit duplication. in behavioral flexibility. In their proposal, aimed at receiving From the social point of view, because the behaviors are variable, rewards or avoiding punishments, the LHb signals information the social interactions of the mice fluctuate, which may lead about the ongoing behavioral state to organize adaptive actions to selection pressure on circuits that are adjustable. As a result in monoaminergic systems. This proposal is worth considering of complicated environment in which mice suffer, the LHb is because the DA and 5-HT systems interact with each other in functionally lateralized instead of having structural asymmetry. a complimentary fashion during behavioral flexibility, such that For future researches, it is worth verifying whether structural balanced increases in DA and 5-HT levels are correlated with asymmetry vs. functional lateralization of Hb circuits are related ideal reversal learning performance in the orbitofrontal cortex to stereotyped vs. flexible behaviors in individuals, and rigidity vs. and the striatum (Doya, 2008; Robbins and Arnsten, 2009; Bari flexibility in social interactions in the group. et al., 2010; Groman et al., 2013; Liu et al., 2014). Therefore, it is rational to consider that the LHb is involved in behavioral choices ETHICS STATEMENT in a flexible manner, as the LHb is not asymmetrically structured, but is functionally lateralized. Animal experiments were carried out in accordance with the National Institute of Health Guide for the care and use of DIFFERENCES IN EVOLUTIONARY laboratory animals. All experimental protocols were approved by STRATEGIES IN THE HABENULA the Committees for Animal Care and Use of the University of Toyama (A2013MED-19, A2015MED-47). All efforts were made BETWEEN ZEBRAFISH AND MICE: to minimize the number of animals used and their suffering. The ASYMMETRY VS. LATERALIZATION scale-eating cichlid Perissodus microlepis is widely distributed in Lake Tanganyika. The species is not protected all up until now Zebrafish and mice are thought to have adopted different (refered FishBase http://www.fishbase.org/summary/8801). strategies for their survival in the Hb structures. The asymmetry of the zebrafish DHb is thought to be a structural representation of functional incompatibility, where the asymmetrical DHb AUTHOR CONTRIBUTIONS causes highly programmed behavioral choices in binary opposition. This enhances ability of information processing HI wrote the manuscript and made the Figures 1–5. TN made by decreasing the circuit path. Moreover, this prevents circuits Figure 1. MK made Figure 3. YT made Figure 2. from being duplicated, reducing costs, and contributing to an increase in survival. Therefore, zebrafish are thought to have ACKNOWLEDGMENTS adopted a structurally fixed strategy. From the circuit point of view, because asymmetrical circuits in the DHb are structured We thank Dr. H. Nishimaru for critically reading the manuscript. in all zebrafish, all are likely to exhibit stereotyped behaviors All authors discussed and commented on the manuscript. This

Frontiers in Neuroscience | www.frontiersin.org 9 January 2017 | Volume 10 | Article 595 Ichijo et al. Evolution of Habenular Asymmetry work was supported by JSPS KAKENHI Grant Numbers Toyama Prefecture Citizens’ Personal Development Foundation 26640009, 26830009, 15H05230, 15K18335, and Inamori (59), Basic Science Research Projects from The Sumitomo Foundation, Narishige Neuroscience Research Foundation, Foundation (140434), and Asahi Glass Foundation (27–11).

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